B. Herzog

Infertility in Cryptorchidism Is Linked to the Stage of Germ Cell Development at Orchidopexy

Background: Cryptorchidism represents the most common endocrine disease in boys, with infertility frequently observed in unilateral as well as bilateral forms. In this study, we examined the role of Ad (dark) spermatogonia for fertility in cryptorchid boys. The hypothesis to be proven was that boys lacking Ad spermatogonia will develop infertility despite a successful orchidopexy at an early age. Methods: To estimate total sperm count, one of the most predictive parameters of male fertility, we analyzed the ejaculatein 218 cryptorchid men and correlated it with the developmental stage of their germ cells at the time of successful surgery. Results: Abnormal sperm concentration (<40 × 106/ejaculate) was found in half of the patients under the study. 47.5% of unilateral and 78% of bilateral cryptorchid males had their sperm concentration in the infertility range according to the WHO standards. If transformation into Ad spermatogonia had occured, age-related differences in the fertility outcome was observed. The younger the unilateral cryptorchid boys were at surgery, the higher their sperm count. Age-related difference was not found in the group of cryptorchid men having had no A dark spermatogonia at time of surgery, indicating that in this group a successful orchidopexy is insufficient to prevent infertility development and, in particular, the development of azoospermia. Conclusion: The presence of Ad spermatogonia at surgery is an excellent prognostic parameter for future fertility. Cryptorchid boys lacking these cells will develop infertility despite successful orchidopexy at an early age.

The Significance of Postnatal Gonadotropin Surge for Testicular Development in Normal and Cryptorchid Testes

Testicular biopsies from 29 infants with cryptorchidism between birth (gestational age as early as 36 weeks) and 9 months of age were compared to 34 biopsies from the testes of boys at postmortem examination, or during operation for a hydrocele or hernia. The total number of germ cells was similar in both groups but normal testes showed a transformation of gonocytes into spermatogonia to an extent that was not seen in the cryptorchid testes. Cryptorchid testes also showed markedly reduced numbers of Leydig cells compared to normal. These postnatal changes occurred in the normal testes at the same time that the increase is seen in luteinizing and follicle-stimulating hormones during the first few months of life and they are believed to be a consequence of this hormonal activity. It is postulated that the postnatal surge of gonadotropins may be responsible for priming the testes for subsequent development and fertility.

Testicular and Vascular Changes in Children and Adults with Varicocele

We analyzed bilateral testicular biopsies of 188 infertile patients with idiopathic left varicocele. The left side had significant pathological tubular testicular changes compared to the right side, whereas in only 7 per cent of the patients tubular damage was more pronounced on the right side. The Leydig cell pathological score was identical in both testes in 95 per cent of the patients. However, the lower the Leydig cell pathological score the better the testicular histology, suggesting an association between Leydig cell score and testicular function. Of the 188 patients 11 boys and 8 adults were randomly selected, and they displayed clear endothelial proliferative lesions of the capillaries at the ultrastructural level. Proliferative endothelial lesions in the patients with varicocele preceded the testicular changes. This, together with the prevalence of tubular damage at the site of the varicocele and the reversibility of these changes postoperatively, emphasizes the deleterious effects of varicocele as a cause of infertility in these patients. Early surgery for boys in whom the first signs of testicular atrophy occur is highly recommended.

Treatment With a Luteinizing Hormone-Releasing Hormone Analogue after Successful Orchiopexy Markedly Improves the Change of Fertility Later in Life

PURPOSE Infertility has been considered a principal complication associated with cryptorchidism. A particularly high incidence of cryptorchid boys lack the priming effect during the first 3 months of life due to low concentrations of gonadotropins and testosterone (inadequate perinatal stimulation of the testes, which causes infertility). This condition causes impaired transformation of gonocytes into fetal spermatogonia. More pronounced hypogonadotropic hypogonadism results in fewer germ cells. Most importantly, cryptorchid boys with fewer than 0.2 cells per tubular cross section have a high probability of being infertile in adulthood, regardless of whether the condition is unilateral or bilateral and despite apparently successful orchiopexy. MATERIALS AND METHODS To counteract the paucity of priming hormones, cryptorchid patients with unilateral or bilateral cryptorchidism and a severe paucity of germ cells were treated with a low dose of the luteinizing hormone-releasing hormone analogue buserelin after successful orchiopexy. We analyzed the spermiograms of these patients, who are now young adults, and compared them to those of 23 other men who also had cryptorchidism with a comparable severe paucity of germ cells but who had not received hormonal treatment after successful orchiopexy. RESULTS Patients who received hormonal therapy after orchiopexy had significantly improved spermiograms compared to those in the control group. Treatment with buserelin increased the number of spermatozoa, improved motility and increased the number of normal forms of spermatozoa. CONCLUSIONS The luteinizing hormone-releasing hormone analogue buserelin, administered as a nasal spray every other day for 6 months following successful orchiopexy, appears to have a long lasting, positive effect on germ cells. Consequently, the prognosis of fertility has been greatly enhanced in patients treated with buserelin.

Subureteral Collagen Injection for the Endoscopic Treatment of Vesicoureteral Reflux in Children. Followup Study of 97 Treated Ureters and Histological Analysis of Collagen Implants

Endoscopic subureteral injection has become an established alternative means for treating vesicoureteral reflux in select children. However, which injection material to use remains a controversy. Polytetrafluoroethylene (Teflon) has been injected in more than a thousand patients with few complications, although experimental and clinical studies have demonstrated migration of the injected particles into distant organs, such as the lungs and the brain, as well as local and metastatic granuloma formation. Therefore, we introduced, following experimental studies in the mini-pig model, glutaraldehyde cross-linked, highly purified bovine collagen for injection. Between June 1988 and October 1991, 97 refluxing ureters in 66 children were treated by endoscopic subureteral collagen injection. In 58.8% of the ureters reflux was cured after 1 and in 77.3% after 2 injections. Considering improvement to grades I and II reflux without further treatment as success, the success rate increased to 68.0% after 1 and to 89.7% after 2 injections. Mean followup was 18.5 months (range 3 to 39 months). After 2 failed injections the patients either returned to antibiotic long-term prophylaxis or the reflux was operatively corrected. The operative procedure was never compromised by the preceding injection. A direct correlation between deficient length of the submucosal tunnel of the intravesical ureter and the iatrogenic malposition of the collagen deposits, and the failures could be demonstrated. Granuloma formation at the site of injection was not found. The results of the histological investigation of the collagen deposits removed at open ureteral reimplantation for failures are reported. It could be demonstrated that endogenous fibroblasts invade the bovine collagen implant and that these cells show active production of new human collagen, types I and III, replacing the implant.

Endoscopic Subureteral Collagen Injection for the Treatment of Vesicoureteral Reflux in Infants and Children

Between June 1988 and September 1994, 100 girls and 32 boys 2 months to 15.5 years old (average 4.9 years) with 204 refluxing ureteral units were treated by endoscopic subureteral collagen injection. The collagen injected was of bovine origin and cross-linked with glutaraldehyde (Zyplast*). Followup ranged from 3 to 75 months (mean 33). Reflux was absent in 62.7% of cases 3 months after 1 endoscopic subureteral injection. Improvement to reflux grades I and II, generally not requiring further treatment, occurred in a further 15.2% of cases. A total of 66 ureters was injected twice. The overall cure rate after 1 or 2 injections was 79.4% 3 months after injection. There was no correlation between the risk of recurrent reflux and initial degree of reflux. Late recurrence of reflux following a reflux-free period occurred in 11.3% of the 204 units during the observation period, which varied from 3 months to 6 1/4 years. Reflux was absent after 1 or 2 injections, including late recurrence, in 70.6% of cases and in an additional 13.2% recurrent reflux was grade I or II, not necessitating any further treatment. Considering these results, subureteral collagen injection remains an adequate method of treatment for vesicoureteral reflux in children.

Histological Behavior of Glutaraldehyde Cross-Linked Bovine Collagen Injected Into the Human Bladder for the Treatment of Vesicoureteral Reflux

Endoscopic subureteral collagen injection has become an accepted means for the treatment of vesicoureteral reflux in children. The aim of this study was to evaluate the histological behavior of glutaraldehyde cross-linked bovine collagen implants. The specimens were harvested from 29 patients who underwent reimplant surgery 2 to 30 months (mean 9.5) after unsuccessful subureteral injection therapy. In addition to routine hematoxylin and eosin staining, a new staining method (solophenyl red 3BL) able to demonstrate selectively neoformation of types I and III human collagen, was applied. Invasion of host fibroblasts into the bovine implant and the formation of endogenous types I and III collagen were demonstrated in all 29 cases. Adverse histological reactions were rare and, if present, they were predominantly of an inflammatory nature.

The Chance for Fertility in Adolescent Boys After Corrective Surgery for Varicocele

We estimated the efficacy of a surgical procedure in adolescent patients with varicocele and left testicular atrophy. A total of 25 young men (mean age 23.6 years) had a complete andrological followup for 10 years after successful ligation of the spermatic vein (according to Ivanissevich) to correct left varicocele and testicular atrophy. Levels of follicle-stimulating hormone, luteinizing hormone and testosterone in the plasma were normal in all cases. Patients were characterized into 2 distinct groups: group A--11 patients with asthenoteratospermia and group B--14 with a normal spermiogram. There was a significant difference between groups A and B in the number of sperm per ejaculate (32 x 10(6) in A and 234.9 x 10(6) in B, p < 0.001). Preoperatively there was no difference between these 2 groups regarding testicular atrophy of the left compared to the right testis (87% in A and 86.4% in B) and the comparative testicular histology of biopsies since the number of Ad spermatogonia per tubule was considerably reduced in all patients (right side 0.68 +/- 0.71 and left side 0.38 +/- 0.39 in A, and right side 0.15 +/- 0.17 and left side 0.14 +/- 0.11 in B). In both groups there was no distinguishable difference in the degree of atrophy of seminiferous tubules or Leydig cells in both testes, or patient age at surgery (mean 13.3 years in A and 12.8 years in B). While the left testis of patients in group B caught up in size to the contralateral testis, the left testicular volume in patients in group A was only 80% of the right testicular volume (p < 0.03, the Fisher test). One patient from group B required a second surgical procedure because of a relapse. Persistent atrophy of the left testis in group A indicates that some patients benefit suboptimally from the conventional surgical procedure.

Hormonal Treatment of Cryptorchidism

60 cryptorchid boys (39 unilateral and 21 bilateral) aged between 10 months and 14 years were treated by conservative methods. All boys received an initial therapy of 200 µg GnRH nasal spray (decapeptide) in each nostril three times daily for 4 weeks. Those who did not respond favorably to the GnRH treatment immediately received a follow-up therapy with 1,500 IU or boys over 7 years 2,000 IU of HCG per week for a total of 3 weeks. Immediately after completion of this therapy, the success rate was 80% (65/81 testes decended). 6 months afterwards 6 of the 48 testes suffered a relapse. Thus, 73% of the testicles were still descended 6 months after completion of therapy.

Endoscopic subureteric collagen injection (SCIN): a new alternative treatment of vesicoureteric reflux in children

Endoscopic subureteric injection has become an accepted form of treatment for vesicoureteric reflux in children in selected cases. However, the commonly injected substance Teflon has raised doubts as to its long-term safety. Glutaraldehyde cross-linked bovine collagen, which is not associated with the feared side effects of Teflon (granuloma formation, particle migration), seems to be an adequate replacement. At the Departement of Paediatric Surgery of the Basel University Childrens Hospital 54 patients with a total of 82 refluxing units were treated with the subureteric collagen injection (SCIN) in the period between June 88 and August 90; 45 patients were female and 9 were male. The average age at treatment was 4.9 years (2 months– 15.2 years). Micturating cystourethrograms performed 3 months after injection showed disapperance of reflux in 61.3% (49 ureters).If improvement to grade I and II reflux was included, the success rate increased to 77.5%. After two SCIN procedures 77.6% of the ureters became free of reflux. Including improvement to grade I and II reflux, the success rate increased to 83.8%. The mean follow-up time was 11.5 months (2–27 months). Injection-related complications were not observed. Although the overall results were not as good as those after surgical correction of reflux and the long-term effects of the collagen implants are not yet known, SCIN seems to be a simple alternative treatment for vesicoureteric reflux in children.